Project Summary Joint damage and synovial inflammation in rheumatoid arthritis (RA) are influenced by genetic and environmental factors. Individual patients and joints have shown variation of response to the same treatment. To reveal the underlying mechanisms, genome-wide characterization of the RA pathogenesis that require small amount of input materials and at relatively low cost is necessary. Currently, RNA-seq and ATAC-seq satisfy these requirements to map transcriptome and open chromatin in the RA samples, which can provide complementary delineation of the pathogenic mechanisms. We propose here to perform RNA-seq and ATAC- seq in fibroblast-like synoviocytes (FLS) for both RA and osteoarthritis (OA) patients. We will develop and improve a new computational pipeline that integrates these data to evaluate each transcription factor's importance in individual patients. By comparing FLS RA and OA samples, we will identify disease-specific regulators in Specific Aim 1. By comparing individual RA patients, we will identify patient-specific regulators in Specific Aim 2. We will perform biologic experiments to validate the top predicted regulators in Specific Aim 3. Once completed, this study will open a new avenue of understanding the regulatory mechanisms underlying RA and dictating the variable responses to treatment in individual patients, which paves the way towards precise and personalized therapy.